Gastrin is a peptide hormone produced by a single gene and synthesised from a precursor peptide preprogastrin, which is processed into progastrin and gastrin peptide fragments of various sizes by sequential enzymatic cleavage. There are 3 main forms of gastrin: gastrin-34 (G34 or ‘big gastrin’), gastrin-17 (G17 or ‘little gastrin’), and gastrin-14 (G14 or ‘minigastrin’). All gastrins have a C-terminal amidated tetrapeptide (Trp-Met-Asp-Phe-NH2), which acts at a specific G protein-coupled gastrin receptor (also called CCK2 receptor; formerly known as CCKB receptor) in the stomach and in the central and peripheral nervous systems.
Gastrin is structurally and functionally related to another peptide hormone, cholecystokinin (CCK), which is also produced by a single gene and processed into several molecular forms by sequential enzymatic cleavage. The main forms in blood and tissue are CCK-58, CCK-33 and CCK-8. All fragments have at their carboxyl terminus the octapeptide Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2, which stimulates specific G protein-coupled CCK1 receptors on pancreatic acinar cells, gall bladder smooth muscle, vagal afferent neurons in the small intestine, and cells in the central nervous system. The C-terminal tetrapeptide (Trp-Met-Asp-Phe-NH2) is identical to that of gastrin. As a result, CCK has weak gastrin-like activity and gastrin has weak CCK-like activity. The common C-terminal tetrapeptide has hindered the development of selective antagonists for the CCK1 or CCK2 receptor, and has confounded assays for CCK, because antibodies to CCK may crossreact with gastrin.
Gastrin stimulates gastric acid secretion via a mechanism involving activation of gastrin (CCK2) receptors.
Gastrin also causes proliferation, migration and differentiation of gastric epithelial cells, and up-regulates various genes, such as chromogranin A (CgA), histidine decarboxylase (HDC), vesicular monoamine transporter 2 (VMAT2), matrix metalloproteinase (MMP)-7, and protein Reg 1A, and stimulates paracrine cascades, including cytokines, growth factors such as trefoil factor, and prostanoids. Gastric acid secretion is regulated by endocrine, paracrine, and neurocrine mechanisms via at least three signalling pathways: gastrin-histamine (stimulation), CCK1/somatostatin (inhibition) and neural networks (both stimulation and inhibition). Different pathways are suppressed or dominate, depending on the circumstances.
Circulating gastrin is increased by: hypoacidity due to autoimmune chronic atrophic gastritis (CAG) or H. pylori-induced gastritis; a gastrinoma in patients with Zollinger-Ellison syndrome (ZES); and acid suppression by histamine H2-receptor antagonists, proton pump inhibitors (PPIs), potassium-competitive acid inhibitors or vagotomy. CAG hypergastrinaemia leads to ECL-cell hyperplasia and, in some patients, development of gastric carcinoids (type 1 neuroendocrine tumours), which are mostly benign but can become malignant. Patients with pernicious anaemia, which is one of the possible clinical presentations of atrophic gastritis, have a nearly seven-fold increased risk of gastric cancer. ZES hypergastrinaemia causes hyperacidity, peptic ulceration and gastric carcinoids (type 2 neuroendocrine tumours), which have greater potential for malignancy, especially in patients with the multiple endocrine neoplasia type 1 gene. H. pylori infection is a major risk factor for peptic ulcer disease and gastric cancer. PPI-induced hypergastrinaemia causes: enterochromaffin-like (ECL)-cell hyperplasia; parietal cell hyperplasia; fundic gland polyps; bone loss, impaired bone quality and bone fractures; and possibly malignant ECL-cell tumours in some patients. PPI withdrawal leads to rebound hyperacidity and, in some people, dyspepsia. Gastrin receptors are also expressed on pancreatic cancer, colonic cancer, medullary thyroid cancer, and Barrett's oesophagus cells. PPI-induced hypergastrinaemia is associated with advanced neoplasia in Barrett's oesophagus. Thus, there are various potential clinical indications for a gastrin/CCK2 receptor antagonist.
A known 1,4-benzodiazepine-derived CCK2 receptor antagonist is L-365,260, which possesses nanomolar affinity at CCK2 receptors and reasonable selectivity (140-fold) versus the CCK1 receptor. However, oral L-365,260 produced only modest and short lasting inhibition of gastrin-stimulated acid secretion in healthy men, and was ineffective in limiting panic attacks in patients, results attributed to its low aqueous solubility and poor oral bioavailability (Murphy et al. Clin Pharmacol Ther 1993; 54: 533-39 and Kramer et al. Biol Psychiatry 1995; 37: 462-466).

Another known 1,4-benzodiazepine-based CCK2 receptor antagonist is YM022. YM022 showed subnanomolar affinity at rat brain CCK2 receptors, which was more than two orders of magnitude higher than that for rat pancreatic CCK1 receptors.

However, YM022 suffered low aqueous solubility and had to be formulated as a solid dispersion to achieve adequate oral bioavailability (Yano et al. Chem Pharm Bull (Tokyo) 1996; 44: 2309-2313).
Subsequently, YF476 was developed, which had a binding affinity at CCK2 receptors similar to that of YM022, but was 5-fold more selective for CCK2 receptors than for CCK1 receptors (Semple et al. J Med Chem 1997; 40: 331-341).

Examples of benzodiazepine derivatives that act as antagonists at CCK2 receptors are also given in U.S. Pat. No. 4,820,834 and European Patents EP 0 628 033 B1 and EP 1 342 719 B1.
Despite considerable effort of pharmaceutical companies for three decades, no CCK2/gastrin receptor antagonist has been developed into a medicine, mainly because of problems with potency, selectivity between CCK1 and CCK2 receptors, agonist activity, solubility, and oral bioavailability.
Accordingly, there remains a need for an efficacious CCK2/gastrin receptor antagonist which can successfully be used in pharmaceutical compositions to provide beneficial properties in terms of pharmacokinetics, improved bioavailability, avoidance of a requirement for administration with food, minimisation of processing steps required in formulation, and the like.
It has been determined that serum concentrations of YF476 were extremely low and very variable when YF476 was administered in a crystalline form to healthy subjects. Bioavailability can be improved by preparing and administering a formulation of amorphous YF476, but this requires stabilisation such as in the form of a solid dispersion on hydroxypropyl methyl cellulose by spray-drying. Even with this processing, bioavailability of YF476 was still low. Because food increased bioavailability of YF476 by 1.6-fold in healthy subjects, it was administered with food in the patient studies. However, it would be beneficial to provide a CCK2/gastrin receptor antagonist where administration with food is not required.
The inventors have now identified a class of compounds that exhibit properties favourable for successful use as a CCK2/gastrin receptor antagonist and, if provided in the form of a pharmaceutical composition for administration to a patient, addresses problems previously hindering successful development of a CCK2/gastrin receptor antagonist into a medicine.